1
Małgorzata Sobieszczańska
1, Sławomir Tubek
2, Monika Daszkiewicz
3Membrane Zinc Transporters Znt-1 and Znt-5
in Circulatory System Pathophysiology
Transportery błonowe cynku ZnT-1 i ZnT-5
w patofizjologii układu krążenia
1 Department of Pathophysiology, Wroclaw Medical University, Poland 2 Department of Internal Diseases, Provincial Hospital in Opole, Poland 3 Military Hospital in Żary, Poland
Abstract
The paper presents current information concerning the significance of membrane zinc transporters in circulatory system pathophysiology. The presence of ZnT-1, ZnT-3, ZnT-5 and ZnT-7 carriers in the heart has been reported. Two of these – ZnT-1 and ZnT-5 – reveal a relationship with some cardiac conditions. ZnT-1 occurs in the cellular membrane, and ZnT-5 in the membrane of cell organelles, including the Golgi apparatus. Elucidating the role of ZNT-1 and other proteins in intracellular zinc contents could have useful implications for the treatment of cardio-vascular diseases (Adv Clin Exp Med 2011, 20, 1, 87–91).
Key words: membrane zinc transporters, ZnT–1, ZnT–5, circulatory system diseases.
Streszczenie
W pracy przedstawiono aktualne dane dotyczące roli błonowych transporterów cynku w patofizjologii układu krążenia. W sercu stwierdza się obecność nośników ZnT–1, ZnT–3, ZnT–5 i ZnT–7. Dwa z nich: ZnT–1 i ZnT–5, wykazują związek z patologiami układu krążenia. ZnT–1 występuje w błonie komórkowej, a ZnT–5 w błonach organelli komórkowych, w tym aparatu Golgiego. Wyjaśnienie roli ZnT–1 i innych białek wpływających na wewnątrzkomórkowe stężenie cynku może mieć istotne znaczenie praktyczne w leczeniu chorób układu sercowo- -naczyniowego (Adv Clin Exp Med 2011, 20, 1, 87–91).
Słowa kluczowe: transportery błonowe cynku, ZnT-1, ZnT-5, choroby układu krążenia.
Adv Clin Exp Med 2011, 20, 1, 87–91 ISSN 1230-025X
rEvIEWS
© Copyright by Wroclaw Medical University
Zinc (Zn) is an essential element in the or-ganism, where it plays numerous functional and structural roles. The human organism has devel-oped efficient mechanisms of zinc homeostasis, so the clinical symptoms of zinc deficit are rarely encountered. Pathological processes such as ar-terial hypertension, diabetes mellitus, obesity or ischemia cause zinc dyshomeostasis: excessive zinc accumulation in cells, which leads to mito-chondrial dysfunction and impairment of energy production. Zn is considered to be the main toxic factor in hypoxic neurons, leading to their death. Taking these considerations into account, there must be efficient mechanisms of homoeostasis in normal physiological conditions to prevent excessive intracellular zinc accumulation. This
is what actually happens: Free zinc levels are in-creased in extracellular space, while the global amount of zinc is much higher in intracellular space. Zinc efflux from cells takes place against the concentration gradient and electrochemical gradient [1, 2].
So far, 24 protein carriers participating in transmembrane zinc transport have been identi-fied on the cell membrane level, including 10 pro-teins shifting zinc from cytoplasm outside the cell (ZnT-1 – a cell membrane transporter) or to inner structures, mainly into the endoplasmic reticulum (the remaining transporters) [5].
The presence of ZnT-1, ZnT-3, ZnT-5 and ZnT-7carriers in the heart has been reported. A correlation between two of them – ZnT-1 and ZnT-5 – and circulatory system pathologies has been observed. ZnT-1 occurs in cell membranes, while ZnT-5 occurs in the membranes of cell or-ganelles, including the Golgi apparatus [5].
In instances of a genetic lack of ZnT-1 in mice, embryonic lethality was observed, whereas the lack of one allele did not result in clinical changes in experimental animals. An increase in ZnT-1 atrial myocytes in the course of atrial fibrillation, and a functional correlation between ZnT-1 and L-type calcium channels were also observed [6, 7].
Experimental studies on rats with chronic hyperaldosteronism have also revealed increased ZnT-1 expression in cardiomyocytes, which de-creased after spironolactone use [8, 9]. In Wistar-Kyoto rats, Zn inhalation caused no significant changes in ZnT-1 expression in the lung or liver, but zinc increased cardiac ZnT-1 at 24th hours, indicat-ing a possible zinc-specific cardiac effect [10].
In the case of ZnT-5, however, it was observed that a genetically conditioned absence results mainly in rapid cardiac deaths in male rats in the course of bradyarrhythmia. This is related to myo-cyte dysfunction in the heart conduction system resulting from the lack of ZnT-5 [11].
During atrial fibrillation, atrial muscle myo-cytes have an increased ZnT-1 level, which sug-gests the activation of mechanisms lowering zinc accumulation in cells. Increased expression of mrNA for ZnT-1 has been observed in the atrial muscles of patients with atrial fibrillation, espe-cially in obese subjects [6]. It can be therefore be concluded that the abnormal bioelectrical function of the myocytes and their excessive tension results in an increase in Zn ion influx into the cell, with a secondary increase in ZnT-1 synthesis as a pro-tective mechanism reducing the toxic effect of ex-cessive intracellular Zn.
A close correlation has been observed between ZnT-1’s participation in electrical remodeling in the heart and L-type voltage dependent calcium channels (LTCC) [7]. Therefore, the higher the ZnT-1 expression, the lower the LTCC activity.
Decreased LTCC activity observed in the atria can be considered as the main cause underlying pa-tients’ susceptibility to atrial fibrillation [7]. Thus, it could be also suggested that higher ZnT-1
ex-pression would result in reduced calcium overload in cardiomyocytes.
In a comparison of obese and normal sub-jects with arterial hypertension, differences have been noted in the Zn efflux from lymphocytes. In these patients, a spironolactone block of aldoster-one receptors resulted in increased zinc content in lymphocytes and increased zinc ion efflux from lymphocytes – i.e., activity reversing the changes in zinc metabolism that occur in arterial hyper-tension. There was a positive correlation between zinc efflux and its level in the cell. A difference in the reaction of normal and obese subjects to spironolactone was also observed: In obese sub-jects, the activity of zinc efflux from lymphocytes was on virtually the same level during a one-week observation, whereas it increased in normal sub-jects [12].
A similar direction of intracellular Zn changes influenced by aldosterone and spironolactone was observed in experimental rats with chronic hyper-aldosteronism, in which increased ZnT-1 expres-sion decreasing under the influence of spironolac-tone was found [8, 9].
On the basis of ZnT-1 behavior in atrial fibril-lation, it can be assumed that the same phenom-enon will take place in ventricular myocytes when their tension is increased (e.g. increased pre-load or sympathetic tension), both in a normal myocar-dium and in the course of cardiectasia. It may be assumed that the higher the ZnT-1 activity, which is most probably genetically conditioned, the lower the activity of toxic intracellular Zn accu-mulation will be, and the slower the development of changes during the course of pathological pro-cesses involving the circulatory system (e.g. myo-cardial ischemic damage, atherosclerosis, arterial hypertension).
Different levels of severity of disturbances in various organs in different patients who are ex-posed to harmful factors of similar intensity and duration can be explained by variations in geneti-cally determined Zn efflux from cells.
Animal studies indicate that there are genetic differences – e.g. a Zn deficit in the diet results in a different reaction in spontaneously hypertensive rats (increased arterial blood pressure) than in Wistar-Kyoto rats (no such reaction) [13].
condi-tions. Earlier observations revealed a correlation between zinc deficit (low serum zinc level, Zn-s) and these phenomena [16–19]. Animal studies have indicated the possibility that prior zinc ad-ministration may considerably reduce the area of myocardial necrosis following closure of the coro-nary artery [20].
Other medicines influencing the renin-angio-tensin-aldosterone system, such as angiotensin-converting enzyme inhibitors and angiotensin re-ceptor blockers, will probably have a similar effect on ZnT-1 expression. Their beneficial effects on or-ganic functional changes are related to the effect of zinc metabolism [21]. With regard to the circulatory system, this affects cardiomyocytes and myocytes, as well as vascular endothelial cells [22–28].
If zinc were to be used as a therapeutic agent, it should be administered intravenously (e.g. in the form of zinc sulphate), which would quickly increase its serum level and lead to increased ZnT-1 activity. Oral administration would not be of much use, due to a lack of increased zinc ab-sorption from the alimentary tract.
rapidly increasing temporary fluctuations in serum zinc levels may influence the nephrotoxic-ity of contrast agents used in imaging studies [29]. This may be related to a delayed adaptive mecha-nism connected with ZnT-1 activity.
In primary arterial hypertension, increased ab-sorption of zinc from the alimentary tract has been recorded, which may testify to a deficit or an in-creased demand for this element [30]. Determining ZnT-1 expression in (e.g.) lymphocytes, along with the curve of zinc absorption from the alimentary tract, could provide a good indication of whether we are dealing with zinc deficit or dyshomeosta-sis. Zinc dyshomeostasis manifesting itself in the course of arterial hypertension may accelerate the development of atherosclerosis, accelerate the age-ing process and predispose the individual to develop type II diabetes and left ventricular failure [31].
regulating changes in zinc metabolism and lowering the level of dyshomeostasis will be pos-sible to achieve, depending on the primary cause, through the administration of medicines directly or indirectly influencing zinc metabolism. Taking into account the toxic effect of excessive intracel-lular Zn2+, an essential element will be to improve
membrane function and the efficiencyof zinc ef-flux into the extracellular space. Since excessive in-tracellular Zn2+ disrupts the mechanisms of oxygen
metabolism, it also diminishes zinc efflux from the cell, and a vicious circle begins. The use of agents affecting intracellular oxygen metabolism, such as pyruvates, decreases zinc accumulation and im-proves cell survival [32].
It may be argued that the main focus of phar-macological and non-pharphar-macological activities aimed at achieving or maintaining zinc homeosta-sis should be the regulation of zinc metabolism by reversing zinc redistribution in the body.
However, with regard to the statement above concerning effective homeostasis mechanisms, chronic zinc supplementation seems to be a rath-er marginal problem in the population, except in cases of chronic dietary zinc deficiency. In certain justified cases, temporary zinc supplementation during a relative deficit may have a positive meta-bolic result, although extensive clinical studies are required. In experimental studies, an increase or decrease in zinc content in extracellular space had an ambiguous effect on the activation or inhibi-tion of mrNA synthesis of particular ZnT trans-port proteins that condition effective zinc efflux from the cell [5]. Moreover, zinc supplementation should also be considered in relation to other mi-croelements in the diet [33].
Currently, intensive studies are being con-ducted concerning the effect of zinc on metabo-lism. In these studies zinc is treated as an element regulating the physiological process of ageing and preventing some conditions, especially arterial hy-pertension, atherosclerosis, impaired immunity and type 2 diabetes. The role of membrane pro-teins transporting zinc is of particular importance in these studies, since this element plays an impor-tant role in maintaining the integrity and function of endothelial cells [31, 33–36].
It may be supposed that the same direction of ZnT-1 changes as in atrial fibrillation (which may be treated as an emergency situation) will occur in other chronic processes in the circulatory system, such as arterial hypertension, atherosclerosis and ischemic cardiomyopathy (post-inflammatory or toxic), as well as in the physiological ageing pro-cess. Due to the gradually increasing insufficiency of processes regulating zinc efflux from cells and its intracellular distribution (mainly with regard to the amount and activity of ZnT-1, but also ZnT-5), a slow process of intracellular zinc accumulation takes place (growing Zn dyshomeostasis), which may be aggravated by zinc deficit. That process may be accompanied by progressive circulatory insufficiency or cell sensitivity to hypoxia [37, 38]. Zn-T functions may also influence the toxicity of other elements, e.g. cadmium [39], as well as the ageing process [40].
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Address for correspondence:
Małgorzata Sobieszczańska Department of Pathophysiology Wroclaw Medical University Marcinkowskiego 1
50-367 Wroclaw Poland
Tel./fax: +48 71 784 12 47 E-mail: [email protected]
Conflict of interest: None declared
